title: Thyroid hormone negatively regulates CDX2 and SOAT2 mRNA expression via induction of miRNA-181d in hepatic cells.
abstract: Thyroid hormones (THs) regulate transcription of many metabolic genes in the liver through its nuclear receptors (TRs). Although the molecular mechanisms for positive regulation of hepatic genes by TH are well understood, much less is known about TH-mediated negative regulation. Recently, several nuclear hormone receptors were shown to downregulate gene expression via miRNAs. To further examine the potential role of miRNAs in TH-mediated negative regulation, we used a miRNA microarray to identify miRNAs that were directly regulated by TH in a human hepatic cell line. In our screen, we discovered that miRNA-181d is a novel hepatic miRNA that was regulated by TH in hepatic cell culture and in vivo. Furthermore, we identified and characterized two novel TH-regulated target genes that were downstream of miR-181d signaling: caudal type homeobox 2 (CDX2) and sterol O-acyltransferase 2 (SOAT2 or ACAT2). CDX2, a known positive regulator of hepatocyte differentiation, was regulated by miR-181d and directly activated SOAT2 gene expression. Since SOAT2 is an enzyme that generates cholesteryl esters that are packaged into lipoproteins, our results suggest miR-181d plays a significant role in the negative regulation of key metabolic genes by TH in the liver.
authors.affiliation: Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, 8, College Road, Singapore 169857, Singapore.
authors.forename: Chui Sun
authors.initials: CS
authors.lastname: Yap
authors.forename: Rohit Anthony
authors.initials: RA
authors.lastname: Sinha
authors.forename: Sho
authors.initials: S
authors.lastname: Ota
authors.forename: Masahito
authors.initials: M
authors.lastname: Katsuki
authors.forename: Paul Michael
authors.initials: PM
authors.lastname: Yen
mesh_terms: D000071616:CDX2 Transcription Factor; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D002785:Sterol O-Acyltransferase / Q000096:biosynthesis* / Q000235:genetics; D013963:Thyroid Hormones / Q000494:pharmacology / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D002785:Sterol O-Acyltransferase; D013963:Thyroid Hormones; D000097587:Sterol O-Acyltransferase 2; C491270:CDX2 protein, human; C540193:MIrn181 microRNA, human
keywords: Cholesterol; Cholesteryl esters; LDL; Liver; T(3); T(4); TH; TR; TRE; Thyroid hormone; VLDL; low density lipoprotein; miRNA; thyroid hormone; thyroid hormone receptor; thyroid hormone response element; thyroxine; triiodothyronine; very low density lipoprotein